A major gap in knowledge exists relating to the mechanisms via which a normal hematopoietic stem cell attains a fully transformed state via preleukemic intermediates. It is now accepted that a key player in this transition is epigenetic plasticity. Identifying the epigenetic mechanisms regulating the transformation of normal to leukemic stem cells will open new avenues for the identification of therapeutics at different stages of disease. A characteristic stem cell-like gene expression pattern is a hallmark of aggressive acute myeloid leukemia. Intriguingly, most of these patients harbour mutations in epigenetic modifiers that directly regulate stemness. What is fundamentally missing is a comprehensive understanding of which chromatin factors are involved in maintaining normal stem cell programs and how they are modulated during leukemic transformation. I recently uncovered a novel epigenetic mechanism of transition to the leukemic-state, mediated by direct chromatin binding of mutant NPM1 and transcriptional regulation of a specific set of stem-cell genes. This discovery, together with cutting-edge ultra-low-input chromatin technologies and our recently developed in vivo models of preleukemia, will serve as the springboard to address these fundamental questions: 1) How are normal hematopoietic stem cell programs regulated at the epigenetic level? 2) What are the epigenetic landscape alterations that govern tumorigenicity? 3) How can we exploit epigenetic dependencies to pharmacologically target the premalignant and/or malignant state? EpiTransformers will delve into the largely unexplored epigenome during the leukemic transformation of rare stem cell populations using cutting-edge epigenetic profiling technologies and sophisticated in vivo models to deconvolute different steps of leukemogenesis and identify cancer specific vulnerabilities. The goal of EpiTransformers is to develop new therapeutic approaches by specific targeting of premalignant leukemic states.